**1. Introduction**

#### **1.1 Early efforts of drug repurposing**

When WHO declared that the COVID-19 pandemic was in place on March 2020, there were no standard drugs available for this new disease. One of the fastest and the most effective solution to face this problem is relying on the drug repurposing effort. Remdesivir is one of the earliest repurposed drug, as it has been originally develop for hepatitis C, and already examined for application in Ebola and Marburg virus infection [1, 2]. In the laboratory setting, remdesivir has been proven to inhibit the RdRp protein of SARS-CoV-2 that is responsible for viral replication, shortens hospitalization period, and is supported with vivid computational model [2–5]. Hence, remdesivir could only be provided in hospital as it should be delivered intravenously to the patients, thus deterring out-patient application [6]. In parallel, some other repurposing efforts are on the way as well.

These anti-worm and anti-parasitic drugs, Ivermectin, Chloroquine, and Hydroxychloroquine, are also repurposed. Although they provide promising in vitro and in vivo leads, there are inconclusive clinical trial results. Moreover, some metaanalysis results provide some leads that are yet to be validated in the clinical trials [7–12]. Hence, there are some repurposed drugs that are efficacious to reduce the severe effects of COVID-19, although they are not anti-viral ones. Dexamethasone, a long-standing standard drug of anti-inflammation and anti-coagulation, could inhibit the 'cytokine storm' of late stage COVID-19 [13]. It also acts as immune modulator as well [14, 15]. Then, Heparin that works as anti-blot clot drug, also deployed to the COVID-19 patients [16–19]. However, during the early phase of COVID-19 pandemics, there are no standard drugs that could provide solid clinical evidence and could be deployed in out-patients.

### **2. Ascendancy of standard drugs for COVID-19**

The development of Paxlovid and Molnupiravir, both of them are synthetic drugs, have enabled new standard due to the emergency FDA's authorization [20, 21]. As nucleoside analogue, molnupiravir has successfully inhibited RdRp protein of SARS-CoV-2 while providing significant clinical trials result for patients with mild-to-moderate symptoms of COVID-19 [22]. Thus, Paxlovid, which is a

combination of two distinctive drugs of nirmatrelvir dan ritonavir, could inhibit SARS-CoV-2's main protease enzyme with retaining its acceptable concentration in the blood, and reduces hospital admission alongside with mortality rate significantly [23, 24]. Hence, both drugs were optimized with rational drug design methods and approved by the FDA with emergency authorization [22–26]. Although remdesivir has provided significant efficacy in the clinical setting, its in-patient setting prevented the wide-spread use. However, the development of oral remdesivir has been devised and the current status is deemed successful in the in vivo trials [27, 28]. Although careful and thorough examination by medical specialist is necessary before deploying those anti-viral drugs, they are considered the available standard drugs for COVID-19 so far.
